Medical diagnostic imaging techniques such as ultrasound imaging and x-ray imaging are extremely valuable tools for the early detection and diagnosis of various disease states of the human body. The use of contrast agents for image enhancement in medical diagnostic imaging procedures is widespread. An excellent background on image enhancement or contrast agents in medical imaging is provided by D. P. Swanson et al, Pharmaceuticals in Medical Imaging, 1990, MacMillan Publishing Company, the disclosure of which is hereby incorporated by reference in its entirety.
In x-ray imaging, transmitted radiation is used to produce a radiograph based upon tissue attenuation characteristics. X-rays pass through various tissues and are attenuated by scattering, i.e., reflection or refraction, or energy absorption. However, blood vessels and body organs, e.g., the liver, exhibit so little absorption of x-ray radiation that radiographs of these body portions are difficult to obtain. To overcome this problem, radiologists introduce an x-ray absorbing medium, i.e., a contrast agent, into body organs and vessels.
Computerized tomography (CT) scanning is a high contrast imaging technique which utilizes x-rays to produce tomographic images of the body's internal structures. Contrast agents used for this purpose must be capable of attenuating x-rays. Contrast agents which are extremely useful are those which are designed to be taken up preferentially by a portion of the body which is desired to be imaged by means of x-ray technology. This lowers the background noise and permits better contrast of the image of the body portion. There is a need for improved x-ray contrast agents for imaging specific portions of the body.
For example, currently there is no completely satisfactory x-ray contrast agent available for imaging the liver. Emulsions of iodinated oils such as iodinated ethyl esters of poppy seed oil and liposomes containing water soluble iodinated contrast agents have been proposed for liver visualization. However, emulsions tend to be unacceptably toxic and liposomes tend to require unacceptably large amounts of lipid to achieve adequate contrast enhancement.
In ultrasound imaging, short pulses of sound waves generated by an ultrasound transducer are directed at an anatomical region of interest. The ultrasound waves, like x-rays, pass through various tissues and are attenuated by scattering or energy absorption. However, in ultrasound imaging, the production of images is based on detecting the reflected portion of the attenuated sound waves.
Whether or not an ultrasound wave will be reflected at a given tissue or tissue component interface depends primarily on the acoustic impedance properties of the respective tissues or tissue components and the angle of incidence of the ultrasound wave with respect to the reflecting surface. Thus, at a given angle of incidence, the greater the difference between acoustic impedance values, the greater the ultrasound reflection. Consequently, the development of ultrasound contrast agents has been based upon attempts to maximize acoustic impedance differences at tissue or tissue component interfaces. Heretofore, the investigation of ultrasound contrast agents has been limited. However, some clinical success has been achieved using gas containing bubbles and lipid emulsions.
Gas containing bubbles and microbubbles, such as those described in U.S. Pat. No. 4,572,203; U.S. Pat. No. 4,718,433; U.S. Pat. No. 4,774,958 and U.S. Pat. No. 4,844,882; tend to be good reflectors of ultrasound waves due to the substantial difference in acoustic impedance between such bubbles and blood. Hand-injection approaches to the generation of intravascular bubbles to enhance ultrasound images generally result in an unsatisfactory, low intensity signal. Further, microbubbles produced by hand injection can provide ultrasound contrast enhancement of the right chamber of the heart, but are generally unable to survive passage through the capillary bed of the lung. Studies have reported that microbubbles of small diameter, i.e., less than 10 microns, produced by the sonification of various surfactant solutions or by precision gas injection microbubble techniques are capable of capillary transmission (Bommer et al, Circulation 1981, 64:200-203; Feinstein et al, J. Am. Coll. Cardiol. 1984, 3:595-600). However, the use of such agents for ultrasound enhancement of the left chamber of the heart following intravenous administration has been extremely limited, due to the lack of availability of precision microbubbles and surfactant formulations indicated and approved for ultrasound image enhancement. Furthermore, gas-containing bubble systems tend to be unstable when subjected to systolic blood pressures and shear. Thus, the overall safety of gas-containing bubble ultrasound contrast enhancement compositions remains a significant concern, particularly when such formulations are introduced into coronary arteries.
In addition to gas-containing bubble systems, lipid emulsions have been investigated as potential ultrasound contrast enhancement agents. Mattrey et al, Radiology, 1987, 163:339-343 have reported preliminary clinical success with the intravenous injection of a perfluorocarbon, i.e., perfluorodecalin-perfluorotripropylamine, emulsion. However, other dense lipid emulsions have failed to produce an increase in echogenicity. Furthermore, nonemulsified perfluorocarbons vaporize at body temperature. Thus, the ultrasound enhancement effects of perfluorocarbon emulsions may be related to breakdown of the emulsion in the RES cells and the subsequent release of perfluorocarbon vapor in the form of microbubbles. Consequently, this approach may not avoid the problems associated with gas containing bubbles.
Thus, there is a need for ultrasound contrast agents which are useful in diagnostic imaging of coronary vessels and the left chamber of the heart and which do not exhibit the problems of the prior art materials.